Sepsis is a serious public health threat for which there is little treatment. In the US alone, sepsis kills over 28% of 751,000 patients annually, and it is the major cause of death and disability for patients in surgical intensive care units. Sepsis is a syndrome in which infectious agents instigate disease, but disease progression is likely mediated by the exaggerated and dysregulated host responses. However, because many patients can recover from the initial stages of sepsis and do not progress into severe sepsis or septic shock, endogenous mechanisms that attenuate disease progression must also exist. Preliminary data show that syndecan-1, a major heparan sulfate proteoglycan (HSPG), attenuates multi-organ dysfunction and lethality in animal models of sepsis. Syndecan-1 is a cell surface HSPG whose extracellular ectodomain is released from the cell surface by metalloproteinase-mediated ectodomain shedding under inflammatory conditions. Preliminary data also indicate that syndecan-1 shedding is activated in endotoxic wild type (WT) mice, and that syndecan-1 ectodomains inhibit endotoxic multi-organ dysfunction and lethality through their heparan sulfate (HS) chains. Further, syndecan-1 null (Sdcl-/-) mice show a higher mortality in Gram positive superantigen-induced toxic shock and cecal ligation and puncture (CLP)-induced sepsis. These data suggest that syndecan-1 and its shedding mediate an important host defense mechanism against sepsis. The goal of this proposal is to define how syndecan-1 attenuates, in part, the highly complex mechanisms of sepsis. Three inter-related hypotheses will be tested in three Specific Aims: 1) Syndecan-1 attenuates endotoxic shock by shedding its ectodomains will be evaluated by determining how transgenic mice overexpressing soluble syndecan-1 ectodomains or nonsheddable syndecan-1 respond to LPS; 2) Specific structural motifs in syndecan-1 HS inhibit endotoxic shock will be tested by defining the HS domain that inhibits endotoxic multi-organ dysfunction and lethality; and 3) Syndecan-1 attenuates CLP-induced sepsis by inhibiting multi-organ dysfunction through its HS chains will be assessed by determining the responses of Sdcl-/- and WT mice to CLP, and by testing the effects of various syndecan-1 HS-related agents in CLP-induced sepsis. These studies, which will define how syndecan-1 functions in sepsis and endotoxic shock, should generate physiologically relevant information to design new therapeutic approaches to attenuate, halt, or reverse sepsis.